Aspirin in Primary and Secondary

Cardiovascular Disease Prevention. Still Four

Questions: About Enteric-Coated, Indicated

Doses, Use in Diabetes, Use in PVD

Carlo Patrono, MD, FESC

Catholic University School of Medicine, Rome, Italy

New York Cardiovascular Symposium

New York, 8th December 2017

I received consultant and speakers fees from Amgen,

AstraZeneca, Bayer and GlaxoSmithKline

I chair the Scientific Advisory Board of the

International Aspirin Foundation

I received grant support for investigator-initiated

research from:

• European Commission, FP6 and FP7 Programmes

• Bayer AG

Disclosure

COOH OCOCH3

Portal

blood ASPIRIN (Acetylsalicylic acid)

Stomach

Small intestine

COOH

OH

CH3COOH+ Acetic acid

COOH

OH

Conjugation

Glucuronide, glycine conjugates (kidney excretion)

Portal blood

Liver

(first-pass effect)

COOH

OCOCH3

CES-2

Salicylic acid (inactive)

Plasma CEs

Salicylic Acid (inactive)

Ser 529–OCOCH3 COX -1 inactive

Ser 529–OH

COOH

OCOCH3

COOH

OH

COX-1 active Carboxyl Esterases

(CE)

Platelets

(portal and systemic blood)

Salicylic acid (inactive)

TXA2

(unstable,

active)

TXB2

(stable,

inactive)

H2O

Patrono et al., JACC 2017;70:1760-76.

Aspirin Has Two Distinct Cellular Targets

Systemic

bioavailability

~ 40%

Bone marrow

megakaryocytes and

platelet precursors

Salicylic acid

Ser –OCOCH3

COX-1/2 inactive

COOH

OCOCH3

COOH

OH

Ser–OH

COOH

OH Salicylic acid

(inactive)

Plasma

esterases

COX-1/2 active

TX

B2 (

ng

/ml)

0

1

2

3

*

*

* * Slope 0.09±0.01 *

Slope 0.06±0.01

* p<0.01 vs lean

patients

BMI 34±4kg/m2,n=18

BMI 23±1.6kg/m2,n=16

*

12h 15h 18h 21h 24h post aspirin

Serum TXB2 Levels are Significantly Higher in

EC Aspirin-Treated Obese vs Lean Non-Diabetic

Patients Over the 12-24h Dosing Interval

Rocca, et al., J Thormb Haemost 2012;10:1220-30.

Obesity and Aspirin PK

Plasma acetylsalicylic acid (ng/ml)

. 0 5

10 15 20

0 12 24 hrs

Time

0

2000

0 4 8 hrs Time

1000

Control subjects

Obese subjects

SerumTXB2

ng/ml

Control subjects Obese subjects

Patrono & Rocca JACC 2017,69:613-15

Antithrombotic Trialists’ Collaboration

Meta-Analysis of Aspirin Trials in High-Risk Patients

(mg daily) Aspirin Control Reduction (SE)

75-150 10.9% 15.2% 32 (6)

160-325 11.5% 14.8% 26 (3)

500-1500 14.5% 17.2% 19 (3)

Any dose 12.9% 16.0% 23 (2)

(2P<0.00001)

1.0 0.5 0.0 1.5 2.0 BMJ 2002;324:71-86

Aspirin dose % Vascular Events % Odds

Odds ratio (CI)

Does One Size Fit All?

Probably yes, because:

a) Inactivation of platelet COX-1 and suppression of

thromboxane production are cumulative upon

repeated daily dosing, and saturable at doses as low

as 30-40 mg daily.

b) There is no evidence that higher doses (e.g., 300-

325 mg) are more effective than lower doses (i.e.,

75-100 mg), and the opposite may be true.

Cumulative Inhibition of Platelet COX-1 by Low Doses of

Aspirin Shifts the Dose-Response Curve by a Factor

Equivalent to the Daily Platelet Turnover

100

80

60

40

20

0

1 10 100 mg Aspirin

ID50=3.2 mg ID50=26 mg

Daily dose

Single dose Percent

inhibition

of serum

TXB2

Patrono et al., Circulation 1985; 72:1177-84

Does One Dosing Regimen Fit All?

Maybe not, because there is substantial interindividual

variability in the rate of recovery of platelet COX-1

activity during the 24-hour dosing interval, perhaps

requiring more frequent dosing (e.g., bid) in patients with

accelerated renewal of the drug target.

COX-1

COX-1

COX-2

T2DM

Healthy

Aspirin 10

8

6

4

2

0 0 2 4 6 8 10 12 14 16 18 20 22 24

Serum

TXB2

ng/ml

Time (h)

Arachidonic Acid

Prostaglandin H2

Thromboxane A2 Thromboxane B2

Platelet aggregation (inactive metabolite)

Platelet Prostaglandin G/H synthase 1

Aspirin

Altered Pharmacodynamics of Low-Dose Aspirin in Type 2 Diabetes

Patrono, Rocca, De Stefano Blood 2013;121:1701-11.

Aspirin

T2DM

Aspirin

0

2

4

6

8

10

12

Healthy

Subjects

CHD PVD CVD

Type 2 Diabetes

Davì et al, N Engl J Med 1990;322:1769-74

Urinary

11-dehydro-

TXB2

nmol/day

Thromboxane Biosynthesis is Enhanced in Type 2

Diabetes with Macrovascular Complications

Mean±SD

n=32

n=25

n=16

n=9

1. Circulation 2015;132:691-718 2. Eur Heart J 2013;34:3035-87

3. Diabet Med 2006;23:579-593 4. Endocr Pract. 2007;13(Suppl 1)

5. CMAJ 2008;179:920-926

Aspirin for Primary Prevention of CVD in Diabetes: Current Guidelines

ADA/AHA1

ESC-EASD2

IDF3

AACE4

Canadian Diabetes Associaton5

1) Low-dose aspirin (75-162 mg/day) is reasonable among those with a 10-year CVD risk of at least 10% and without an increased risk of bleeding.

2) Low-dose aspirin is reasonable in adults with diabetes mellitus at intermediate risk (10-year CVD risk, 5-10%) Antiplatelet therapy for primary prevention may be considered in high-risk patients with DM on an individual basis

Recommended in people at high risk

Recommended

No evidence, use left to individual clinical judgment

Ongoing Randomized Trials of Aspirin vs Placebo:

High-Risk Individuals

Study Regimen(s) Treatment

duration

N Eligibility Primary endpoint End

date

ARRIVE EC Aspirin 100 mg

vs Placebo

5y 12,000 10-20% estimated

10y risk of CHD

MI, stroke, CV

death, unstable

angina, TIA

2018

ASPREE EC Aspirin 100 mg

vs Placebo

5 y

19,000 Elderly, no

diabetes or CVD

Death, dementia or

significant disability

2018

ASCEND EC Aspirin 100 mg

vs Placebo

(ω3FA vs P)

7.5 y 15,000 Diabetes, no CVD MI, stroke or TIA,

or CV death

2018

Patrono, JACC 2015;66:74-85

Berger et al, JAMA 2009;301:1909-19.

Effect of Aspirin on Major Vascular Events in PAD Trials

Clopidogrel vs Aspirin in Patients at Risk of

Ischemic Events (CAPRIE)

6431 Pts with recent

ischemic stroke

6302 Pts with recent

myocardial infarction

6452 Pts with

symptomatic PAD

Clopidogrel

75 mg Aspirin

325 mg

Clopidogrel

75 mg

Aspirin

325 mg

Clopidogrel

75 mg Aspirin

325 mg

Follow-up: 1.91 yr (1-3yr)

Primary end-point: cluster of ischemic stroke, MI, or vascular death

Primary analysis: intention-to-treat comparison for the entire patient

population and for each of the clinical categories

Lancet 1996;348:1329-39.

0 10 -40 -30 -20 -10 20 30 40

Aspirin better Clopidogrel better

Stroke

PAD

MI

Relative Risk Reduction and 95% CI

All patients

Lancet 1996;348:1329-39.

Kaplan–Meier Analysis of the Primary End Point

Hiatt WR et al. N Engl J Med 2017;376:32-40

100

90

80

70

60

50

40

30

20

10

0 0 3 6 9 12 15 18 21 24 27 30 33 36

13

12

11

10

9

8

7

6

5

4

3

2

1

0 0 3 6 9 12 15 18 21 24 27 30 33 36

Ticagrelor

Clopidogrel

Hazard ratio, 1.02 (95% CI, 0.92-1.13)

P=0.65

Patients

with

Primary

End Point

(%)

Months since Randomization

Ticagrelor 6930 6792 6679 6583 6474 6360 6248 6143 6036 5802 3830 2089 865

Clopidogrel 6955 6830 6744 6639 6538 6455 6353 6237 6111 5835 3834 2055 852

No. At Risk

2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease

COR LOE Recommendations

I A Antiplatelet therapy with aspirin alone (range 75-325 mg per day) or

clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke,

and vascular death in patients with symptomatic PAD.

IIa C-EO In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is

reasonable to reduce the risk of MI, stroke, or vascular death.

IIb B-R In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of

antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is

uncertain.

IIb B-R The effectiveness of dual antiplatelet therapy (DAPT) (aspirin and

clopidogrel) to reduce the risk of cardiovascular ischemic events in patients

with symptomatic PAD is not well established.

IIb C-LD DAPT (aspirin and clopidogrel) may be reasonable to reduce the risk of

limb-related events in patients with symptomatic PAD after lower extremity

revascularization.

IIb B-R The overall clinical benefit of vorapaxar added to existing antiplatelet

therapy in patients with symptomatic PAD is uncertain.

Gerhard-Hermann et al. Circulation 2017;135:e726–79.

Eikelboom et al, N Engl J Med 2017; 377:1319-30.

COMPASS: Aspirin, Rivaroxaban, or Both

in Stable CAD and PAD

COMPASS: CAD and PAD

Subgroups for Primary Outcome

Outcome

R + A

N=9,152

A

N=9,126

Rivaroxaban + Aspirin

vs. Aspirin

N

(%)

N

(%)

HR

(95% CI)

CAD 347

(4.2%)

460

(5.6%)

0.74

(0.65-0.86)

PAD 126

(5.1%)

174

(6.9%)

0.72

(0.57-0.90)

COMPASS Investigators, Lancet Nov 10, 2017 (Epub ahead of print)

Conclusions 1. Obesity and diabetes are independent and possibly

additive determinants of poor aspirin responsiveness,

limiting the extent and/or duration of platelet inhibition,

and possibly requiring different dosing strategies, well

beyond the uncertain effect of enteric coating.

2. Except for a loading dose in the setting of ACS or acute

ischemic stroke, prescribing aspirin 325 mg daily for long-

term treatment would not produce any additional benefit

above and beyond 75-100 mg, while exposing the patient

to unnecessary GI damage and undue bleeding

complications, as well as to potential negative

interactions with ACE-inhibitors and ticagrelor.

Conclusions

3. Use of aspirin for primary CV prevention in diabetes is not

uniformly recommended because of inadequate

evidence. The results of the ASCEND trial should clarify

its benefit/risk profile in this setting.

4. Use of aspirin in PAD is controversial and is associated

with high residual CV risk. Combination of aspirin with a

factor Xa inhibitor may improve clinical outcomes in this

setting.